Glaucoma is a disease of the eye characterized by increased intraocular pressure. The intraocular pressure (IOP) in the hypertensive eye causes atrophy and excavation of the ocular nerve thereby producing the visual field defects associated with glaucoma. If untreated, increased IOP may cause blindness. It is known that IOP may be affected by application of various adrenergic agents. Adrenergic agents exert their activity by interaction with receptors (adrenoceptors). The agents may be characterized by their activity, i.e., as stimulating agents (agonists) or blocking agents (antagonists), and by the specific type of adrenoceptors upon which they act.
Adrenoceptors are of two primary types: alpha and beta. Based upon the selectivity of the receptors for a series of agonists and antagonists, the alpha adrenoceptors are divided into subtypes, designated alpha.sub.1 and alpha.sub.2.
Alpha agonists preferentially stimulate each type of adrenoceptor with varying degrees of specificity rather than exclusivity. Therefore selectivity for an adrenoceptor subtype is relative. Alpha agonists with relative selectivity for the alpha.sub.2 subtype are efficacious in lowering IOP and are part of current ocular hypertension therapy, including glaucoma therapy. However, some undesirable side effects are associated with the use of these compounds for these indications. For example, some alpha agonists are known to cause significant and undesirable cardiovascular depression and mydriasis (pupil dilation). These side effects are mediated by central nervous system alpha.sub.2 adrenoceptors and ocular alpha.sub.1 adrenoceptors, respectively.
Because of this, efforts are being made to develop more selective alpha.sub.2 agonists which remain localized in the ocular environment. In addition, methods and compositions are being developed which potentiate the IOP effect of the alpha.sub.2 agonist allowing a reduction in dose which reduces the side effects associated with its use.
It has now been discovered that Na.sup.+ /H.sup.+ exchange inhibitors, such as various amiloride analogs, e.g., 5-(N,N-hexamethylene) amiloride, 5-(N-ethyl-N-isopropyl) amiloride and 5-(N,N-dimethyl) amiloride, although substantially inactive by themselves in lowering IOP, improve the ocular hypotensive profile of various alpha.sub.2 agonists when co-administered with the alpha.sub.2 agonist. Co-administering a Na.sup.+ /H.sup.+ exchange inhibitor mitigates, reduces or eliminates undesirable side effects associated with conventional alpha.sub.2 agonist therapy for treatment of ocular hypertension by enabling treatment with lower alpha.sub.2 agonist dosages. In addition, co-administration of an alpha.sub.2 agonist with a Na.sup.+ /H.sup.+ exchange inhibitor enables equivalent or improved therapeutic treatment of ocular hypertension as compared to using equivalent or higher dosages of the alpha.sub.2 agonist alone.